Preparation method of gamma-vinylidene-butenoic acid lactone and / or benzofulvene compounds

Abstract

The present invention belongs to the technical fields of organic synthesis, fine chemicals and pharmaceutical synthesis, and specifically relates to a method for preparing γ-vinylidene-butenoic acid lactones and / or benzofulvene compounds. The method utilizes an acid-catalyzed dehydration rearrangement reaction of cyclopropenyl alcohol derivatives to achieve the synthesis of two important compounds, γ-vinylidene-butenoic acid lactone and benzofulvene, under the condition of a "one-pot reaction"; at the same time, the preparation method is used as an important synthesis strategy to achieve the efficient synthesis of the anti-inflammatory drug rofecoxib and the benzofulvene natural product anmindenol A.

Description

Technical Field

[0001] The invention belongs to the technical fields of organic synthesis, fine chemical industry and pharmaceutical synthesis, and specifically relates to a method for preparing gamma-vinylidene-butenoic acid lactones and / or benzofulvene compounds. Background Art

[0002] As an important basic unit structure, the γ-vinylidene-butenoic acid lactone structure is the core structural skeleton of some drug molecules and natural products (such as Figure 1 These compounds often exhibit many unique biological activities and properties. For example, chloranthalactone A of the oleander-type sesquiterpenes has anti-inflammatory and antifungal biological activities (Agric.Biol.Chem.,1981,45,1447-1453.), and has attracted attention in the field of natural product total synthesis (Org.Lett.,2011,13,5406-5408.); elem-1,3,7,8-tetraen-8,12-olide is a compound isolated from turmeric essential oil, which has anticancer, antiviral and anti-inflammatory effects (Fitoterapia,2015,103,143-148.); dehydromenthol is a coumarin compound extracted from mint, which has strong antibacterial activity (Flavour Frag. J., 2002, 17, 218-226.); rubrolides are natural products isolated from the metabolites of New Zealand marine sac animals and have strong antibacterial activity (Marine drugs, 2020, 18, 337.); cadiolides are natural products isolated from the metabolites of marine sac animals and have good antibacterial activity (J. Nat. Prod., 2012, 75, 2049-2054.); vallapin has insect repellent activity; 1-epimenverin B and menverins C are active natural products extracted from the marine mollusk Schistosoma verrucosum (Helvetica, 2008, 91, 111-117.); Atractylenolide I I) is a sesquiterpene obtained from the root of Atractylodes macrocephala, which has multiple biological activities such as neuroprotection, anti-allergy, anti-inflammatory and anti-cancer. At the same time, Atractylodes macrocephala lactone I is an antagonist of TLR4, which can reduce the phosphorylation levels of JAK2 and STAT3 in A375 cells. Rofecoxib is a non-steroidal anti-inflammatory drug and a selective inhibitor of cyclooxygenase-2. It is commonly used in clinical practice for osteoarthritis, acute pain and primary dysmenorrhea; rofecoxib is also a structural analogue of γ-vinylidene-butenoic acid lactone.

[0003] Similarly, benzofulvene structure is also a very important class of organic compounds as the core structure skeleton of some active biological molecules and natural products. For example, the anti-inflammatory drugs Sulindac and Sulindacsulfone are non-steroidal anti-inflammatory drugs (such as Figure 2 ); benzofulvene natural products with unique structures and good biological activities have attracted much attention, including anmindenol A, nicotianasesterpene A and nicotianasesterpenes B and natural products II, III, IV (as shown in the attached Figure 2 As shown in the figure, anmindenol A was first isolated and identified from the marine-derived bacteria Streptomyces. Anmindenol A can effectively inhibit inducible nitric oxide synthase (iNOS) without showing any obvious cytotoxicity (J.Nat.Prod.,2014,77,1528-1531.); nicotianasesterpene A and nicotianasesterpenes B were extracted from tobacco leaves (Nat.Prod.Res.,2016,30,2545-2550.), and natural products II, III, and IV are three benzofulvene natural products extracted from the plant Polygonum aviculare (BMC Cancer, 2017, 17, 694-706.), they have anticancer activity against cancer cells, but low activity against normal 3T3 cells. Among them, natural product IV has the strongest antiproliferative potential against non-small cell lung cancer cells (NCI-H460), can induce cell apoptosis, inhibit cancer cell migration, change gene expression, and lead to cell apoptosis and angiogenesis. They have similar structures and also show a variety of biological activities, such as anti-inflammatory, antiviral and anti-cancer. Similarly, the total synthesis research of this type of compound has also attracted much attention in the field of organic synthesis. In 2019, the Yun group of Busan University in South Korea achieved their total synthesis in 6 steps (anmindenol A) and 9 steps (nicotianasesterpene A and B) respectively (J.Org.Chem., 2019, 84, 10953-10961; Eur.J.Org.Chem., 2019, 6714-6719.).

[0004] For the synthesis of γ-vinylidene-butenoic acid lactone structure, the existing preparation methods mainly rely on the derivatization improvement of existing oxygen-containing heterocycles, but this often requires multiple steps to synthesize its precursors. Therefore, the existing preparation methods have the disadvantages of long steps, low overall yield, poor selectivity, poor substrate applicability, and poor functional group tolerance caused by strong acid systems. Some synthesis methods may also use some precious metals or highly toxic compounds, which increases the reaction cost and limits the synthetic application in drug molecules and active natural products.

[0005] The existing synthesis methods of benzofulvene and its derivatives can be roughly divided into five categories according to the different initiation modes of the key cyclization reaction: photocatalytic or thermally initiated allene-ene-eneyne or enediyne cyclization reaction, transition metal-catalyzed tandem cyclization reaction, nucleophilic or electrophilic reagent attack initiated cyclization reaction, free radical initiated cyclization reaction, and Lewis acid promoted cyclization reaction. In the above methods, the substrates for synthesizing benzofulvene basically contain C≡C triple bonds or allenes, and the synthesis of the substrates often requires multiple steps, which brings about the disadvantages of long steps, low overall yield, poor selectivity, poor substrate applicability, and poor functional group tolerance caused by strong acid systems. Some synthesis methods may also use some precious metals or highly toxic compounds, which increases the reaction cost and limits the synthetic application in drug molecules and active natural products.

[0006] From the perspective of drug design, the presence of γ-vinylidene-butenoic acid lactone and benzofulvene structures in active molecules has an important influence on biological activity. Therefore, developing new synthetic strategies for these two types of structures has great medicinal value. Summary of the invention

[0007] In order to solve the above problems, the present invention proposes a method for preparing γ-vinylidene-butenoic acid lactone and benzofulvene compounds, and the method is applied to the preparation of the drug rofecoxib and the natural product anmindenol A. The method utilizes acid-catalyzed dehydration rearrangement reaction of cyclopropenyl alcohol derivatives to achieve the synthesis of two important organic intermediates, γ-vinylidene-butenoic acid lactone and benzofulvene, under the condition of "one-pot reaction"; at the same time, the preparation method is used as an important synthesis strategy to achieve the efficient synthesis of the anti-inflammatory drug rofecoxib and the benzofulvene natural product anmindenol A.

[0008] The present invention is achieved through the following technical solutions:

[0009] A method for preparing γ-vinylidene-butenoic acid lactones and / or benzofulvene compounds, the preparation method comprising reacting a reaction substrate under specified conditions, quenching, extracting, drying and filtering after the reaction, and then removing excess solvent and purifying and separating to obtain the γ-vinylidene-butenoic acid lactones and / or benzofulvene compounds;

[0010] The γ-vinylidene-butenoic acid lactone compound includes rofecoxib;

[0011] The benzofulvene compound includes anmindenol A.

[0012] Furthermore, the preparation of the γ-vinylidene-butenoic acid lactone and benzofulvene compounds is to place a cyclopropenyl alcohol derivative a (compound a) with different substitutions in a reaction solvent, then add an acid for catalysis, and after the reaction is completed by thin layer chromatography (TLC), the reaction is quenched, extracted, concentrated, and column chromatographed to obtain γ-vinylidene-butenoic acid lactone compound b and benzofulvene compound c, respectively.

[0013] Furthermore, the reaction formula of the method is as follows:

[0014]

[0015] Where: R 1 An aromatic ring (such as a benzene ring, a naphthalene ring, etc.);

[0016] R 2 is an alkyl group (such as methyl, ethyl, isopropyl, butyl, tert-butyl, etc.);

[0017] R 3 is aromatic, alkyl or hydrogen;

[0018] R 4 is an aromatic group or an alkyl group;

[0019] R 5 It is an aromatic group or an alkyl group.

[0020] Furthermore, the reaction solvent includes: one or more of toluene, benzene, xylene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, ethyl acetate and n-hexane.

[0021] Furthermore, the acid is a protonic acid or a Lewis acid, including: CH3SO3H, p-TsOH, Cu(OTf)2, Yb(OTf)3, In(OTf)3, Hf(OTf)4, TiCl4, FeCl3, AlCl3, BF3·OEt2.

[0022] Furthermore, the preparation method uses cyclopropenyl alcohol derivatives as reaction substrates to synthesize γ-vinylidene-butenoic acid lactone compounds and benzofulvene compounds through rearrangement, which has not been reported before, is the first time, and is highly innovative and creative; cyclopropene compounds have extremely high reaction activity and are widely used as intermediates to construct various organic compounds. They are hot spots and gold mines in the field of organic synthesis, and how to accurately control the bond breaking and ring opening mode of cyclopropene is extremely challenging; the method of the present invention uses the intramolecular hydroxyl leaving method to accurately control the ring opening direction, and the highly active intermediates produced can be used for subsequent rearrangement conversion reactions, which has not been reported before, and is also its main innovation; in the preparation method, the cyclopropenyl alcohol derivative substrate can be quickly and efficiently synthesized by many known methods, and then the synthesis of γ-vinylidene-butenoic acid lactone compounds and benzofulvene compounds can be quickly and efficiently achieved by acid-catalyzed rearrangement, the steps are short, and many unfavorable factors in the existing literature mentioned above are avoided.

[0023] Another object of the present invention is to provide a method for preparing the natural product anmindenol A, wherein the method for preparing anmindenol A adopts the above method, but with a different substrate; the method for preparing anmindenol A comprises:

[0024] Step 1: Dissolve 4-methyl-1-pentyn-3-ol and methyl p-tolyldiazoacetate (Compound 1) in DCE (1,2-dichloroethane), react under blue light and room temperature, remove excess solvent after the reaction, and purify and separate to obtain Compound 27a;

[0025] The specific contents include: 4-methyl-1-pentyn-3-ol (100 mg, 1.02 mmol) and compound 1 (775 mg, 4.07 mmol) are dissolved in 10 ml DCE (1,2-dichloroethane), irradiated under 470 nm blue light, reacted at room temperature for 12 hours, and the reaction progress is monitored by thin layer chromatography (TLC); after the reaction, the excess solvent is removed by vacuum concentration using a rotary evaporator, and the product is purified and separated on a chromatography column, and the developing solvent is PE (petroleum ether): EA (ethyl acetate) = 10:1 to PE (petroleum ether): EA (ethyl acetate) = 6:1, to obtain compound 27a, which is a yellow viscous liquid (257.4 mg, 81%);

[0026] Step 2: Under inert gas conditions, the compound is dissolved in toluene, BF3·OEt2 (boron trifluoride etherate) is added dropwise, and the mixture is reacted at a constant temperature (120° C.); after the reaction, the mixture is quenched, extracted, dried, and filtered, and then the excess solvent is removed and purified to obtain compound 27b and compound 27c; both compound 27b and compound 27c are light yellow solids;

[0027] The specific contents include: under the protection of inert gas, in a 25 ml reaction tube, compound 27a (1.49 mmol, 388.5 mg) was dissolved in toluene (8 ml), and then BF3·OEt2 (4.48 mmol, 0.55 ml) was slowly added dropwise at room temperature, and then the temperature was raised to 120°C for reaction for 1 hour, and the reaction progress was monitored by TLC (thin layer chromatography); after the reaction was completed, 20 ml of saturated sodium bicarbonate aqueous solution was added to quench, and EA (ethyl acetate) was used for extraction 3 times ( 10ml×3), the organic phase solvents were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure on a rotary evaporator to remove excess solvent, and the product was purified and separated on a chromatography column, the developing solvent was PE (petroleum ether): EA (ethyl acetate) = 80:1 to PE (petroleum ether): EA (ethyl acetate) = 20:1, and a light yellow solid 27b and a light yellow solid 27c were obtained (27b: 87.8 mg, 25.77%; 27c: 152.7 mg, 42.3%, total yield 68.07%);

[0028] Step 3: Compound 27c is prepared into a solution, DIBAL-H (diisobutylaluminum hydride) is added dropwise to the solution of compound 27c at -40°C and stirred, and after the reaction, the mixture is quenched, extracted, dried and filtered, and then the excess solvent is removed and purified to finally obtain the Anmindenol A; the Anmindenol A is a white solid;

[0029] The specific contents include: under the protection of inert gas, in a 25 ml reaction tube, compound 27c (0.25 mmol, 60 mg) was dissolved in DCM (5 ml), and then DIBAL-H (diisobutylaluminum hydride, 1 M, 0.62 mmol, 0.62 ml) was slowly added dropwise at -40°C, and the reaction was stirred at this temperature for 4 hours, and the reaction progress was monitored by TLC. After the reaction was completed, 15 ml of saturated sodium bicarbonate aqueous solution was added to quench, and DCM was extracted 3 times (20 ml×3), the organic phase solvent was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by a rotary evaporator to remove excess solvent, and the product was purified and separated on a chromatographic column, and the developing solvent was PE:EA=6:1, and a white solid Anmindenol A (26.3 mg, yield 49%) was obtained.

[0030] Furthermore, the synthetic route of the preparation method of anmindenol A is as follows:

[0031]

[0032] Another object of the present invention is to provide a method for preparing rofecoxib, wherein the method for preparing rofecoxib adopts the above-mentioned method, but the substrate is different; the method for preparing rofecoxib comprises:

[0033] S1: irradiating a solution containing compound 2 and compound 3 with blue light (470 nm), reacting at room temperature, removing excess solvent after the reaction, and purifying and separating to obtain compound 28a, wherein compound 28a is a yellow solid;

[0034] The compound 2 is The compound 3 is

[0035] The specific contents include: dissolving compound 2 (500 mg, 2.10 mmol) and compound 3 (1.11 g, 6.30 mmol) in 25 ml of DCE, irradiating with 470 nm blue light, reacting at room temperature for 12 hours, and monitoring the reaction progress by TLC; after the reaction, concentrating under reduced pressure with a rotary evaporator to remove excess solvent, and purifying and separating the product on a chromatography column, with the developing solvent being PE:EA=6:1 to PE:EA=4:1, to obtain compound 28a as a yellow solid (811.6 mg, 82%);

[0036] S2: Compound 28a is prepared into a solution, and BF3·OEt2 is added dropwise to the solution of compound 28a at a constant temperature (-20°C) for reaction. After the reaction, the solution is quenched, extracted, dried and filtered, and then the excess solvent is removed and purified to obtain compound 28b and compound 28c. Both compound 28b and compound 28c are light yellow solids.

[0037] The specific contents include: under the protection of inert gas, in a 25 ml reaction tube, compound 28a (1.50 mmol, 579.7 mg) is dissolved in toluene (10 ml), and then BF3·OEt2 (4.50 mmol, 0.56 ml) is slowly added dropwise at -20°C, and then the reaction is continued at -20°C for 4 hours, and the reaction progress is monitored by TLC; after the reaction is completed, 30 ml of saturated sodium bicarbonate aqueous solution is added to quench, and EA is extracted 3 times (30 ml×3), the organic phase solvent is combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by a rotary evaporator to remove excess solvent, and the product is purified and separated on a chromatographic column, and the developing solvent is PE:EA=20:1 to PE:EA=10:1, and a light yellow solid 28b and a light yellow solid 28c (28b: 313.7 mg, 59%; 28c: 182.4 mg, 33%, total yield 92%) can be obtained;

[0038] S3 retro-aldol condensation reaction: Compound 28b is prepared into a solution of compound 28b, mixed with toluenesulfonic acid to obtain a reaction mixture, and the reaction mixture is allowed to react at a constant temperature (100° C.), quenched, extracted, dried and filtered after the reaction, and then excess solvent is removed and purified and separated to finally obtain rofecoxib, which is a light yellow solid;

[0039] The specific contents include: in a 25 ml reaction test tube, compound 28b (0.42 mmol, 150 mg) is dissolved in a mixed solution of DMF (3 ml) and water (1 ml), p-toluenesulfonic acid (0.63 mmol, 108.5 mg) is added, and then the temperature is raised to 100°C for reaction for 12 hours, during which the reaction progress is monitored by TLC. After the reaction is completed, 15 ml of saturated sodium bicarbonate aqueous solution is added for quenching, and EA is extracted 3 times (20 ml×3), the organic phase solvent is combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by a rotary evaporator to remove excess solvent, and the product is purified and separated on a chromatographic column, and the developing solvent is PE:EA=3:1, and a light yellow solid rofecoxib (110.9 mg, yield 84%) can be obtained.

[0040] Furthermore, the synthetic route of the preparation method of rofecoxib is as follows:

[0041]

[0042] The preparation method and application of γ-vinylidene-butenoic acid lactone and benzofulvene compounds of the present invention have at least the following beneficial technical effects:

[0043] The present invention uses easily available, differently substituted cyclopropenyl alcohol derivatives as initial raw materials, undergoes a dehydration rearrangement reaction under acid catalysis, and through different rearrangement paths, can "one pot" realize the construction of two types of compounds, γ-vinylidene-butenoic acid lactone and benzofulvene. This preparation method has the advantages of wide substrate applicability, high total yield, novel and efficient method, easy preparation of raw materials used, easy acquisition of catalysts, simple operation, short steps, and easy industrial production. At the same time, the synthesis method is used as an important synthesis strategy to realize the efficient synthesis of the anti-inflammatory drug rofecoxib and the benzofulvene natural product anmindenol A, and the total synthesis steps are only 3 steps, which further highlights the practicality and efficiency of the synthesis method. It has extremely high value for the drug utilization of these two natural products. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The diagram is a schematic diagram of the molecular structure of γ-vinylidene-butenoic acid lactones and related natural products involved in the background technology of the present invention.

[0045] Figure 2It is a schematic diagram of the molecular structure of benzofulvene natural products involved in the background technology of the present invention.

[0046] Figure 3 Schematic diagram of the preparation process of the natural product Anmindenol A in the embodiment of the present invention.

[0047] Figure 4 is the H NMR spectrum of compound 1b in the embodiment of the present invention ( 1 H NMR spectra of compound 1b in CDCl3 (600MHz)).

[0048] Figure 5 is the carbon NMR spectrum of compound 1b in the embodiment of the present invention ( 13 C NMR spectra of compound 1b in CDCl3 (150MHz)).

[0049] Figure 6 is the H NMR spectrum of compound 1c in the embodiment of the present invention ( 1 H NMR spectra of compound 1c in CDCl3 (600MHz)).

[0050] Figure 7 is the carbon NMR spectrum of compound 1c in the embodiment of the present invention ( 13 C NMR spectra of compound 1c in CDCl3 (150MHz)).

[0051] Figure 8 is the H NMR spectrum of compound 2c in the embodiment of the present invention ( 1 H NMR spectra of compound 2c in CDCl3 (600MHz)).

[0052] Fig. 9 is the carbon NMR spectrum of compound 2c in the embodiment of the present invention ( 13 C NMR spectra of compound 2c in CDCl3 (150MHz)).

[0053] Fig.10 is the H NMR spectrum of compound 4b in the embodiment of the present invention ( 1 H NMR spectra of compound 4b in CDCl3 (600MHz)).

[0054] Fig.11is the carbon NMR spectrum of compound 4b in the embodiment of the present invention ( 13 C NMR spectra of compound 4b in CDCl3 (150MHz)).

[0055] Fig.12 is the H NMR spectrum of compound 4c in the embodiment of the present invention ( 1 H NMR spectra of compound 4c in CDCl3 (600MHz)).

[0056] Fig.13 is the carbon NMR spectrum of compound 4c in the embodiment of the present invention ( 13 C NMR spectra of compound 4c in CDCl3 (150MHz)).

[0057] Fig.14 is the H NMR spectrum of compound 5b in the embodiment of the present invention ( 1 H NMR spectra of compound 5b in CDCl3 (600MHz)).

[0058] Fig.15 is the carbon NMR spectrum of compound 5b in the embodiment of the present invention ( 13 C NMR spectra of compound 5b in CDCl3 (150MHz)).

[0059] Fig.16 is the H NMR spectrum of compound 5c in the embodiment of the present invention ( 1 H NMR spectra of compound 5c in CDCl3 (600MHz)).

[0060] Fig.17 is the carbon NMR spectrum of compound 5c in the embodiment of the present invention ( 13 C NMR spectra of compound 5c in CDCl3 (150MHz)).

[0061] Fig.18 is the H NMR spectrum of compound 8b in the embodiment of the present invention ( 1 H NMR spectra of compound 8b in CDCl3 (600MHz)).

[0062] Fig.19 is the carbon NMR spectrum of compound 8b in the embodiment of the present invention ( 13C NMR spectra of compound 8b in CDCl3 (150MHz)).

[0063] Fig. 20 is the H NMR spectrum of compound 8c in the embodiment of the present invention ( 1 H NMR spectra of compound 8c in CDCl3 (600MHz)).

[0064] Fig.21 is the carbon NMR spectrum of compound 8c in the embodiment of the present invention ( 13 C NMR spectra of compound 8c in CDCl3 (150MHz)).

[0065] Fig. 22 is the nuclear magnetic resonance hydrogen spectrum of the natural product anmindenol A in the embodiment of the present invention ( 1 H NMRspectra of anmindenol A in CDC13 (600MHz)).

[0066] Fig.23 is the carbon NMR spectrum of the natural product anmindenol A in the embodiment of the present invention ( 13 C NMRspectra of anmindenol A in CDC13 (150MHz)).

[0067] Fig.24 is the nuclear magnetic resonance hydrogen spectrum of rofecoxib in the embodiment of the present invention ( 1 H NMR spectra of Rofecoxib in DMSO-d6 (600MHz)).

[0068] Fig.25 is the carbon NMR spectrum of rofecoxib in the embodiment of the present invention ( 13 C NMR spectra of Rofecoxib in DMSO-d6 (150MHz)).

[0069] Fig.26A This is the single crystal spectrum of compound 8b in the example of the present invention.

[0070] Fig.26B This is the single crystal spectrum of compound 8c in the example of the present invention. DETAILED DESCRIPTION

[0071] In order to make the purpose, technical solution and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0072] On the contrary, the present invention covers any substitution, modification, equivalent method and scheme made on the essence and scope of the present invention as defined by the claims. Further, in order to make the public have a better understanding of the present invention, some specific details are described in detail in the following detailed description of the present invention. Those skilled in the art can fully understand the present invention without the description of these details.

[0073] The following examples serve to illustrate the present invention. In the examples, unless otherwise indicated, parts are by weight, percentages are by weight, and temperatures are in degrees Celsius. The relationship between parts by weight and parts by volume is the same as the relationship between grams and cubic centimeters.

[0074] Example 1

[0075] In this embodiment, compound a (1.0 mmol) was dissolved in toluene (5.0 mL) in a reaction test tube, and then kept warm at -20°C for 10 min, and then BF3·OEt2 (boron trifluoride etherate, 3 mmol, 0.37 mL) was slowly added dropwise, and then stirred at -20°C for 2 h. After the reaction, the product was quenched, extracted, concentrated, and purified and separated on a chromatography column to obtain compound b and compound c, respectively. The application examples of different substitutions of a are shown in Table 1 below:

[0076]

[0077]

[0078]

[0079]

[0080]

[0081] The physical properties and structural characterization data of the products in Table 1 above are as follows:

[0082] In No. 1, a milky white solid 1b and a yellow solid 1c (1b: 171.3 mg, 59%, 1c: 100.4 mg, 33%, total yield 92%) can be obtained. Compound 1b: 1H NMR (600MHz, CDCl3) δ7.35-7.31(m,2H),7.21(d,J=7.5Hz,5H),7.13(d,J=6.6Hz,2H),2.40(s,3H),2.08(s,3H),1.47(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.7, 149.3, 144.3, 139.0, 130.3, 130.0, 129.8, 129.2, 128.5, 128.3, 128.2, 125.7, 21.5, 21.3, 19.4. Compound 1c: 1 H NMR (600MHz, CDCl3) δ7.92(d,J=7.6Hz,1H),7.78(d,J=7.7Hz,1H),7.32(t,J=7.4Hz,1H),7.28(d,J=7.6Hz,1H),7. 20(d,J=7.8Hz,2H),7.14(d,J=7.9Hz,2H),3.68(d,J=17.3Hz,3H),2.51(s,3H),2.41(s,3H),1.69(d,J=6.2Hz,3H). 13 CNMR(150MHz,CDCl3)δ165.8,153.6,149.4,139.1,136.9,136.4,135.9,1 29.4,128.8,128.4,126.5,125.38,123.9,121.9,51.1,27.1,26.4,21.4.

[0083] In No. 2, a milky white solid 1b and a yellow solid 2c (1b: 163.3 mg, 56%, 2c: 91.9 mg, 29%, total yield 85%) can be obtained. Compound 2c: 1 H NMR (600MHz, CDCl3) δ7.85(t,J=14.6Hz,1H),7.68(d,J=7.7Hz,1H),7.22(t,J=7.5Hz,1H),7.18(t,J=7.5Hz,1H),7.09(d,J=7 .6Hz,2H),7.04(d,J=7.7Hz,2H),4.02(q,J=7.0Hz,2H),2.40(s,3H),2.30(d,J=13.3Hz,3H),1.61(s,3H),0.99-0.92(m,3H). 13C NMR (150MHz, CDCl3) δ165.5,153.4,149.,139.4,136.9,136.5,136.2,136.0,1 29.9,128.8,128.6,126.6,125.5,124.0,121.9,60.0,27.2,26.5,21.5,14.0.

[0084] In No. 3, a milky white solid 1b and a yellow solid 3c (1b: 157.6 mg, 54%, 3c: 115.3 mg, 35%, total yield 89%) were obtained. Compound 3c: 1 H NMR (600MHz, CDCl3) δ7.86(d,J=7.4Hz,1H),7.67(d,J=7.7Hz,1H),7.22(t,J=7.5Hz,1H),7.17(t,J=7.6Hz,1H),7.09(d,J=7.7H z,2H),7.03(d,J=7.8Hz,2H),4.92(dt,J=12.4,6.2Hz,1H),2.39(s,3H),2.31(s,3H),1.61(s,3H),0.95(dd,J=6.3,1.6Hz,6H). 13 C NMR (150MHz, CDCl3) δ165.04,153.07,148.34,139.49,136.76,136.40,136.36,135.95,13 0.35,128.73,128.68,126.52,125.42,124.00,121.84,67.36,27.12,26.41,21.66,21.44.

[0085] In No. 4, a milky white solid 4b and a yellow solid 4c (4b: 174.2 mg, 56%, 4c: 95.6 mg, 30%, total yield 86%) were obtained. Compound 4b: 1 H NMR (600MHz, CDCl3) δ7.33 (dd, J=7.4, 4.4Hz, 2H), 7.23 (d, J=6.5Hz, 2H), 7.12 (d, J=6.0Hz,2H),6.89(td,J=8.7,2.1Hz,2H),2.41(s,3H),2.08(s,3H),1.47(s,3H). 13C NMR (150MHz, CDCl3) δ 168.6, 163.4, 161.7, 149.0, 144.2, 139.2, 131.1, 131.0, 130.2, 130.0, 128.4, 126.1, 126.0, 115.4, 115.2, 21.5, 21.3, 19.4. Compound 4c: 1 HNMR(600MHz, CDCl3)δ7.86(dd,J=8.4,5.8Hz,1H),7.47(d,J=10.7Hz,1H),7.20(d,J=7.8Hz,2H), 7.12(d,J=7.9Hz,2H),7.02(t,J=8.7Hz,1H),3.66(s,3H),2.47(s,3H),2.41(s,3H),1.70(s,3H). 13 C NMR (150MHz, CDCl3) δ165.7,155.2,149.4,137.5,137.4,137.1,136.0,136.0,135.7,135.2,1 35.2,129.0,128.8,128.5,122.9,122.8,113.2,113.0,111.7,111.6,51.3,27.1,26.6,21.5.

[0086] In No. 5, a milky white solid 5b and a yellow solid 5c (5b: 104.1 mg, 34%, 5c: 168.8 mg, 52%, total yield 86%) were obtained. Compound 5b: 1 H NMR (600MHz, CDCl3) δ7.25-7.21(m,1H),7.16-7.12(m,3H),7.08(d,J=7.9Hz,2H),7 .03(t,J=7.4Hz,1H),6.96(t,J=9.1Hz,1H),2.34(s,3H),2.10(s,3H),1.55(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.4, 149.5, 144.2, 139.3, 134.3, 130.4, 130.1, 130.0, 128.5, 128.5, 128.4, 126.5, 126.0, 21.6, 21.4, 19.4. Compound 5c: 1H NMR (600MHz, CDCl3) δ7.52(d,J=7.8Hz,1H),7.17(q,J=8.0Hz,5H),6.94(t,J =9.0Hz,1H),3.66(d,J=14.5Hz,3H),2.43(s,3H),2.36(s,3H),1.73(s,3H). 13 C NMR (150MHz, CDCl3) δ165.5,155.7,149.8,137.5,137.2,137.1,135.7,135. 5,131.22,128.9,128.7,128.4,126.3,124.2,122.8,51.2,27.2,26.6,21.5.

[0087] In No. 6, a milky white solid 6b and a yellow solid 6c (6b: 182.6 mg, 56%, 6c: 103.2 mg, 30%, total yield 87%) were obtained. Compound 6b: 1 H NMR (600MHz, CDCl3) δ7.28(d,J=8.7Hz,2H),7.23(d,J=7.8Hz,2H),7.17(d,J=8.7Hz,2H),7.11(d,J=8.0Hz,2H),2.40(s,3H),2.08(s,3H),1.48(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.4, 149.5, 144.2, 139.3, 134.3, 130.4, 130.1, 130.0, 128.5, 128.5, 128.4, 126.5, 126.0, 21.6, 21.4, 19.4. Compound 6c: 1 H NMR (600MHz, CDCl3) δ7.73(d,J=8.2Hz,1H),7.62(s,1H),7.16(d,J=8.1Hz,1H),7.09(d, J=7.6Hz,2H),7.01(d,J=7.7Hz,2H),3.54(s,3H),2.35(s,3H),2.29(s,3H),1.58(s,3H). 13 C NMR (150MHz, CDCl3) δ165.5,155.7,149.8,137.5,137.2,137.1,135.7,135. 5,131.2,128.9,128.7,128.4,126.3,124.2,122.8,51.2,27.2,26.6,21.5.

[0088] In No. 7, a milky white solid 7b and a yellow solid 7c (7b: 65.6 mg, 20%, 7c: 196.8 mg, 58%, total yield 78%) were obtained. Compound 7b: 1 H NMR (600MHz, CDCl3) δ7.34 (d, J=8.0Hz, 1H), 7.20 (dd, J=11.2, 4.2Hz, 1H), 7.1 4-7.02(m,5H),7.00(d,J=7.6Hz,1H),2.31(s,3H),2.11(s,3H),1.57(s,3H). 13 C NMR (150 MHz, CDCl3) δ 167.5, 152.6, 144.4, 139.1, 134.4, 131.8, 129.9, 129.7, 129.5, 129.4, 128.2, 126.6, 126.6, 21.5, 21.2, 19.7. Compound 7c: 1 H NMR (600MHz, CDCl3) δ7.66 (d, J = 7.6Hz, 1H), 7.26-7.14 (m, 6H), 3.66 (s, 3H), 2.45 (s, 3H), 2.37 (s, 3H), 1.75 (s, 3H). 13 C NMR (150MHz, CDCl3) δ168.0,152.2,142.9,138.2,137.5,136.2,135.0,134. 0,132.3,129.1,128.9,127.4,126.5,126.2,122.6,52.1,26.8,26.5,21.5.

[0089] In No. 8, yellow solid 8b and orange solid 8c (8b: 65.7 mg, 19%, 8c: 195.6 mg, 55%, total yield 74%) were obtained. 1 H NMR (600MHz, CDCl3) δ7.82-7.78(m,1H),7.75(dd,J=12.5,5.5Hz,2H),7.47-7.41(m,2H),7.32(d,J=7. 5Hz,1H),7.14(d,J=6.8Hz,1H),7.05(dd,J=30.7,22.5Hz,4H),2.24(s,3H),2.15(s,3H),1.59(s,3H). 13C NMR (150 MHz, CDCl3) δ 168.7, 152.8, 144.7, 138.9, 133.6, 132.0, 129.7, 129.2, 129.1, 128.6, 128.5, 127.8, 126.4, 126.1, 125.9, 125.6, 125.2, 31.8, 29.8, 21.4, 21.3, 19.8; Compound 8c: 1 H NMR (600MHz, CDCl3) δ8.00(d,J=8.6Hz,1H),7.93(d,J=7.6Hz,1H),7.86(d,J=8.0Hz,1H),7.74(d,J=8.6Hz,1H),7. 46-7.41(m,2H),7.24(d,J=7.8Hz,2H),7.19(d,J=7.7Hz,2H),3.71(s,3H),2.60(s,3H),2.40(s,3H),1.83(s,3H). 13 C NMR (150MHz, CDCl3)δ169.8,153.7,141.9,137.2,136.4,134.9,134.4,133.5,133.3,132.9,129.2,129.1,128.6,127.0,126.2,126.0,125.3,123.8,122.6,52.1,27.2,26.6,21.5. Compounds 8b (7 mg) and 8c (7 mg) were dissolved in a mixed solvent (1.5 mL petroleum ether + 0.1 mL ethyl acetate + 0.3 mL dichloromethane) and the solvent was slowly evaporated to obtain their respective single crystal structures (see the attached manual). Fig.26A and 26B ).

[0090] Yellow solid 9b and orange solid 9c (9b: 207.1 mg, 56%, 9c: 131.7 mg, 34%, total yield 90%) were obtained from compound 9b: 1 H NMR (600MHz, CDCl3) δ7.33(d,J=8.6Hz,2H),7.22(dd,J=11.6,8.3Hz,4H),7.11(d,J=7.9Hz,2H),2.40(s,3H),2.08(s,3H),1.47(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.3, 149.6, 144.3, 139.3, 131.4, 130.7, 130.1, 130.0, 129.0, 128.3, 126.6, 126.0, 122.7, 21.6, 21.4, 19.5. Compound 9c:1 H NMR (600MHz, CDCl3) δ7.89(s,1H),7.79(d,J=8.2Hz,1H),7.42(d,J=8.2Hz,1H),7.19(d,J=7.7Hz,2 H),7.11(d,J=7.8Hz,2H),3.64(d,J=9.8Hz,3H),2.48(s,3H),2.39(d,J=16.3Hz,3H),1.69(s,3H). 13 C NMR (150MHz, CDCl3) δ165.6,155.9,149.8,138.0,137.7,137.2,135.8,135. 5,129.3,129.0,128.8,128.4,127.1,123.3,119.5,51.3,27.4,26.7,21.5.

[0091] From No. 10, light yellow solid 10b and orange solid 10c (10b: 99.6 mg, 31%, 10c: 215.2 mg, 64%, total yield 95%) were obtained. Compound 10b: 1 H NMR (600MHz, CDCl3) δ7.31(d,J=8.8Hz,2H),7.22(d,J=7.8Hz,2H),7.13(d,J=7.9H z,2H),6.73(d,J=8.8Hz,2H),3.74(s,3H),2.40(s,3H),2.06(s,3H),1.45(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.9, 159.6, 147.6, 144.4, 138.9, 130.7, 130.5, 129.9, 128.5, 126.6, 124.7, 122.5, 113.7, 55.3, 21.6, 21.3, 19.3. Compound 10c: 1 HNMR (600MHz, CDCl3) δ7.82(d,J=8.4Hz,1H),7.35(d,J=2.2Hz,1H),7.19(d,J=7.8Hz,2H),7.13(d,J=8. 0Hz, 2H), 6.87 (dd, J = 8.5, 2.3Hz, 1H), 3.88 (s, 3H), 3.66 (s, 3H), 2.46 (s, 3H), 2.40 (s, 3H), 1.68 (s, 3H). 13C NMR (150MHz, CDCl3) δ166.0,158.3,153.2,148.1,137.6,136.9,136.4,136.1, 132.6,129.2,128.9,128.7,122.5,112.0,110.8,55.8,51.2,27.1,26.6,21.5.

[0092] Compound 11b can be used to obtain a brown solid 11b and a yellow solid 11c (11b: 102.3 mg, 30%, 11c: 146.6 mg, 42%, total yield 72%). 1 H NMR (600MHz, CDCl3) δ8.05(d,J=8.9Hz,2H),7.51(d,J=8.9Hz,2H),7.26(d,J=7.8Hz,2H),7.12(d,J=7.9Hz,2H),2.42(s,3H),2.12(s,3H),1.52(s,3H). 13 C NMR (150 MHz, CDCl3) δ 167.8, 150.7, 147.1, 144.2, 139.9, 136.8, 130.3, 129.9, 129.5, 129.2, 128.1, 125.0, 123.4, 21.6, 21.6, 19.6. Compound 14c: 1 H NMR (600MHz, CDCl3) δ8.68(d,J=1.7Hz,1H),8.22(dd,J=8.6,2.0Hz,1H),8.05(d,J=8.6Hz,1H),7 .23(d,J=7.8Hz,2H),7.13(d,J=7.9Hz,2H),3.68(s,3H),2.63(s,3H),2.42(s,3H),1.77(s,3H). 13 CNMR (150MHz, CDCl3) δ165.1,159.5,154.4,145.8,144.8,137.8,135.9,135 .4,134.9,129.2,128.5,128.1,122.3,122.0,119.1,51.6,27.6,27.0,21.6.

[0093] In compound 12, a milky white solid 12b and a yellow solid 12c (12b: 134.7 mg, 44%, 12c: 121.3 mg, 38%, total yield 81%) were obtained. At the same time, according to the NMR spectrum analysis, it was found that there were isomers in 12c, and the ratio was about 1.8:1. Compound 12b: 1H NMR (600MHz, CDCl3) δ7.24(d,J=7.6Hz,2H),7.19-7.10(m,4H),7.06(d,J=10.6Hz,1H),6.90(t,J=7.6Hz,1H),2.41(s,3H),2.09(s,3H),1.48(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.3, 163.26, 161.6, 150.0, 144.2, 139.4, 130.0, 130.0, 129.7, 129.6, 128.3, 126.9, 124.9, 116.2, 115.3, 21.6, 21.5, 19.4. Compound 12c: 1 H NMR(600MHz, CDCl3)δ7.69(dt,J=15.9,5.8Hz,2H),7.65(dd,J=9.7,1.6Hz,1H),7.31-7.24(m,1H),7.20(d,J=7.6Hz,3H),7.1 2(d,J=7.8Hz,3H),6.98-6.91(m,2H),3.67(d,J=9.3Hz,3H),3.64(s,2H),2.47(s,3H),2.40(s,4H),1.68(s,3H),1.66(s,2H). 13 C NMR (150MHz, CDCl3) δ165.7,165.5,156.0,154.1,150.6,150.9,137.2,137.2,135.8,135.7,129. 00,128.97,128.5,128.4,124.9,124.8,112.0,111.9,109.4,109.3,51.3,51.3,27.2,26.5,21.6.

[0094] From No. 13, light yellow solid 13b and orange solid 13c (13b: 101.0 mg, 32%, 13c: 192.8 mg, 58%, total yield 89%) were obtained. Compound 13b: 1 H NMR (600MHz, CDCl3) δ7.22(t,J=7.8Hz,1H),7.09(d,J=7.8Hz,2H),7.06(d,J=7.8Hz,2H),7.02(d,J=7.4H z,1H),6.83(t,J=7.5Hz,1H),6.79(d,J=8.3Hz,1H),3.58(s,3H),2.31(s,3H),2.08(s,3H),1.54(s,3H). 13C NMR (150 MHz, CDCl3) δ 168.5, 157.4, 150.4, 144.6, 138.6, 131.4, 130.5, 130.0, 129.0, 128.4, 127.2, 124.6, 120.4, 119.3, 111.2, 55.4, 21.4, 21.1, 19.7. Compound 13c: 1 H NMR(600MHz, CDCl3) δ7.39(d,J=7.7Hz,1H),7.23-7.18(m,3H),7.15(d,J=7.4Hz,2H),6 .81(d,J=8.2Hz,1H),3.85(s,3H),3.67(s,3H),2.45(s,3H),2.37(s,3H),1.75(s,3H). 13 C NMR (150MHz, CDCl3) δ168.8,152.6,150.5,139.6,137.8,137.0,135.9,134.6, 131.9,129.1,129.0,127.6,126.9,117.6,109.4,56.1,51.9,26.6,26.3,21.5.

[0095] In No. 14, a milky white solid 14b and a yellow solid 14c (14b: 197.5 mg, 65%, 14c: 73.0 mg, 23%, total yield 88%) were obtained. Compound 14b: 1 H NMR (600MHz, CDCl3) δ7.23(dd,J=13.6,7.3Hz,4H),7.13(d,J=6.9Hz,2H),7.02(d,J=7.7Hz,2H),2.40(s,3H),2.27(s,3H),2.07(s,3H),1.46(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.8, 148.5, 144.4, 138.9, 138.3, 130.6, 129.8, 129.0, 128.9, 128.5, 127.1, 127.1, 125.1, 21.5, 21.4, 21.3, 19.3. Compound 14c: 1 H NMR(600MHz, CDCl3) δ7.79(d,J=7.8Hz,1H),7.60(s,1H),7.19(d,J=7.8Hz,2H),7.1 3(d,J=7.6Hz,3H),3.66(s,3H),2.50(s,3H),2.46(s,3H),2.40(s,3H),1.68(s,3H). 13C NMR (150MHz, CDCl3) δ166.0,153.1,148.8,136.9,136.8,136.6,136.4,136.2,1 35.1,129.4,128.9,128.6,127.3,125.1,121.8,51.2,27.3,26.5,22.2,21.54.

[0096] From No. 15, light yellow solid 15b and yellow solid 15c (15b: 128.4 mg, 36%, 15c: 119.0 mg, 32%, total yield 68%) were obtained. Compound 15b: 1 H NMR (600MHz, CDCl3) δ7.45 (s, 4H), 7.24 (d, J = 7.8Hz, 2H), 7.12 (d, J = 7.9Hz, 2H), 2.41 (s, 3H), 2.10 (s, 3H), 1.50 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ 168.2, 150.7, 144.2, 139.5, 133.7, 130.1, 129.8, 129.4, 128.3, 127.7, 125.8, 125.1, 125.1, 125.1, 125.1, 21.6, 21.5, 19.5. Compound 15c: 1 H NMR (600MHz, CDCl3) δ8.05-8.00(m,2H),7.58(d,J=8.1Hz,1H),7.22(d,J=7.8Hz ,2H),7.13(d,J=7.9Hz,2H),3.67(s,3H),2.56(s,3H),2.42(s,3H),1.73(s,3H). 13 C NMR (150MHz, CDCl3) δ165.5,156.9,150.9,142.1,137.5,135.9,135.8,135.4,1 29.1,128.7,128.4,123.6,123.6,122.1,120.6,120.5,51.4,27.4,26.8,21.6.

[0097] From No. 16, light yellow solid 16b and yellow solid 16c (16b: 69.1 mg, 19%, 16c: 216.3 mg, 56%, total yield 75%) were obtained. Compound 16b: 1H NMR (600MHz, CDCl3) δ7.54(dd,J=7.9,1.0Hz,1H),7.18-7.05(m,6H),6.97(dd,J=7.5,1.7Hz,1H),2.31(s,3H),2.11(s,3H),1.56(s,3H). 13 C NMR (150 MHz, CDCl3) δ 167.3, 152.2, 144.4, 139.1, 132.8, 131.9, 131.7, 130.1, 130.0, 129.3, 127.2, 126.6, 124.4, 21.5, 21.2, 19.7. Compound 16c: 1 H NMR(600MHz, CDCl3) δ7.73(d,J=7.8Hz,1H),7.40(d,J=8.0Hz,1H),7.22-7.15(m ,4H),7.09(t,J=7.9Hz,1H),3.68(s,3H),2.47(s,3H),2.38(s,3H),1.75(s,3H). 13 C NMR (150MHz, CDCl3) δ167.9,152.2,143.2,138.4,137.9,137.6,135.0,134. 0,133.5,130.8,129.1,128.9,126.6,123.2,114.8,52.2,26.8,26.5,21.5.

[0098] Light yellow solid 17b and orange solid 17c were obtained from compound 17. (17b: 45.7 mg, 12%, 17c: 302.8 mg, 77%, total yield 89%). 1 H NMR (600MHz, CDCl3) δ7.24(d,J=6.9Hz,2H),7.15(d,J=7.5Hz,2H),6.64(s,2H),3.76(s,3H),3.55(s,6H),2.36(s,3H),2.06(s,3H),1.46(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.4, 152.6, 148.3, 144.0, 138.9, 1380, 130.9, 129.9, 128.4, 126.2, 125.6, 125.2, 106.3, 60.8, 55.7, 21.3, 21.2, 19.2. Compound 17c: 1H NMR (600MHz, CDCl3) δ7.35 (s, 1H), 7.18 (d, J = 7.4Hz, 2H), 7.11 (d, J = 6.8Hz, 2H), 3.94 (d, J = 1.0Hz, 3H), 3. 91(d,J=1.3Hz,3H),3.78(d,J=1.3Hz,3H),3.58(d,J=1.3Hz,3H),2.40(s,3H),2.33(s,3H),1.62(s,3H). 13 C NMR (150MHz, CDCl3) δ166.1,153.2,153.0,150.7,149.1,141.0,137.0,136.5,136.1 ,135.9,128.8,128.6,127.7,121.0,101.7,61.5,60.4,56.3,51.2,29.8,25.6,21.5.

[0099] In No. 18, a milky white solid 18b and a yellow solid 18c (18b: 148.4 mg, 74%, 18c: 43.3 mg, 20%, total yield 94%) were obtained. Compound 18b: 1 H NMR (600MHz, CDCl3) δ7.91(d,J=7.3Hz,2H),7.75(s,1H),7.41(t,J=7.5Hz,2H),7.36(t,J=7.3Hz,1H),2.05(s,3H),2.01(s,3H). 13 C NMR (150 MHz, CDCl3) δ 169.1, 144.7, 131.6, 130.2, 129.2, 129.2, 128.7, 127.0, 123.3, 19.0. Compound 18c: 1 H NMR(600MHz, CDCl3) δ7.97(d,J=7.5Hz,1H),7.66(d,J=7.7Hz,1H),7.60(s,1H),7.2 3(dd,J=16.0,8.5Hz,1H),7.21-7.15(m,1H),3.83(s,3H),2.40(s,3H),2.29(s,3H). 13 C NMR (150MHz, CDCl3) δ165.6,150.8,140.0,135.8,135.8,135.6,130.0,126.6,125.5,123.5,122.3,51.6,25.7,23.8.

[0100] In No. 19, a milky white solid 19b and a yellow solid 19c (19b: 191.6 mg, 65%, 19c: 76.1 mg, 25%, total yield 90%) were obtained. Compound 19b: 1 H NMR (600MHz, CDCl3) δ7.32-7.28(m,2H),7.26-7.20(m,5H),7.13(t,J=8.3Hz,2H),2.09(s,3H),1.48(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.4, 164.0, 162.3, 147.9, 144.2, 130.7, 130.6, 129.7, 129.2, 128.6, 128.3, 127.9, 125.9, 116.6, 116.4, 21.4, 19.4. Compound 19c: 1 H NMR (600MHz, CDCl3) δ7.94(d,J=7.6Hz,1H),7.79(d,J=7.6Hz,1H),7.31(dt,J=21.7,7.5Hz,2 H),7.22(dd,J=7.7,5.6Hz,2H),7.10(t,J=8.3Hz,2H),3.66(s,3H),2.51(s,3H),1.69(s,3H). 13 C NMR (150MHz, CDCl3) δ165.8,163.2,161.6,153.9,147.9,139.0,136.5,135.9,13 5.0,130.4,130.4,126.8,125.8,124.1,122.2,115.34,115.2,51.3,27.3,26.6.

[0101] From No. 20, light yellow solid 20b and yellow solid 20c (20b: 128.9 mg, 42%, 20c: 136.2 mg, 43%, total yield 85%) were obtained. Compound 20b: 1 H NMR (600MHz, CDCl3) δ7.33 (dd, J=5.9, 2.3Hz, 2H), 7.24-7.19 (m, 3H), 7.16 (d ,J=7.9Hz,2H),6.94(d,J=7.9Hz,2H),3.84(s,3H),2.09(s,3H),1.51(s,3H). 13C NMR (150 MHz, CDCl3) δ 168.7, 160.2, 149.0, 144.5, 130.1, 130.0, 129.2, 128.3, 128.2, 127.3, 125.6, 125.3, 114.6, 55.4, 21.4, 19.5. Compound 20c: 1 H NMR (600MHz, CDCl3) δ7.91(d,J=7.6Hz,1H),7.78(d,J=7.7Hz,1H),7.35-7.27(m,2H),7.17( d,J=8.5Hz,2H),6.94(d,J=8.5Hz,2H),3.86(s,3H),3.67(s,3H),2.50(s,3H),1.71(s,3H). 13 C NMR (150MHz, CDCl3) δ166.0,159.1,153.7,149.1,139.2,136.7,136.0,131. 1,129.9,129.7,126.6,125.5,124.1,122.0,113.7,55.3,51.3,27.3,26.6.

[0102] From compound No. 21, a light yellow solid 21b and an orange solid 21c (21b: 168.4 mg, 61%, 21c: 62.5 mg, 22%, total yield 82%) were obtained. 1 H NMR (600MHz, CDCl3) δ7.45-7.39(m,3H),7.32(dd,J=6.5,2.8Hz,2H),7.26(dd,J=6.3,2.9Hz,2H),7.23-7.16(m,3H),2.09(s,3H),1.45(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.6, 149.0, 144.2, 133.5, 129.9, 129.20, 129.16, 129.1, 128.7, 128.4, 128.2, 127.3, 125.8, 21.4, 19.3. Compound 21c: 1 H NMR (600MHz, CDCl3) δ7.94 (d, J = 7.5Hz, 1H), 7.79 (d, J = 7.7Hz, 1H), 7.39 (t, J = 7. 3Hz,2H),7.37-7.28(m,3H),7.25(s,1H),3.63(s,3H),2.51(s,3H),1.68(s,3H). 13C NMR (150MHz, CDCl3) δ165.9,153.9,149.1,139.2,139.2,136.5,136.0,129.7,128.7,128.2,127.4,126.7,125.6,124.1,122.1,51.3,27.3,26.5.

[0103] From No. 22, light yellow solid 22b and yellow solid 22c (22b: 192.8 mg, 65%, 22c: 87.5 mg, 28%, total yield 94%) were obtained. Compound 22b: 1 H NMR (600MHz, CDCl3) δ7.45-7.41(m,1H),7.35-7.30(m,2H),7.23(d,J=5.2Hz,3H),7.20-7.13(m,3H),2.10(s,3H),1.52(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.3, 160.4, 158.8, 143.7, 142.5, 131.5, 130.5, 129.7, 128.9, 128.7, 128.4, 125.8, 125.0, 116.4, 116.2, 21.3, 18.5. Compound 22c: 1 H NMR(600MHz, CDCl3) δ7.99(d,J=7.5Hz,1H),7.80(d,J=7.6Hz,1H),7.37-7.29(m,3H ),7.22-7.16(m,2H),7.12(t,J=8.9Hz,1H),3.66(s,3H),2.53(s,3H),1.78(s,3H). 13 C NMR (150MHz, CDCl3) δ165.5,160.5,158.9,153.8,142.4,139.0,136.2,135.9,1 30.8,129.6,126.7,125.9,124.2,124.1,122.4,115.5,115.4,51.4,27.3,25.6.

[0104] From No. 23, a light yellow solid 23b and an orange solid 23c (23b: 132.8 mg, 43%, 23c: 163.9 mg, 51%, total yield 94%) were obtained. Compound 23b: 1H NMR (600MHz, CDCl3) δ7.39 (t, J = 7.9Hz, 1H), 7.37-7.30 (m, 2H), 7.24-7.15 (m, 3H), 7.0 5(d,J=7.6Hz,1H),6.96(dd,J=7.9,4.4Hz,2H),3.75(s,3H),2.07(s,3H),1.46(s,3H). 13 C NMR (150 MHz, CDCl3) δ 168.9, 157.0, 146.3, 144.1, 130.8, 130.4, 129.8, 128.8, 128.3, 128.2, 127.7, 124.9, 122.7, 121.3, 111.2, 55.7, 21.2, 18.4. Compound 23c: 1 H NMR (600MHz, CDCl3) δ7.95(d,J=7.5Hz,1H),7.78(d,J=7.7Hz,1H),7.34(t,J=7.8Hz,1H),7.30(t,J=7.5Hz,1H),7.28-7.24(m ,2H),7.08(d,J=7.3Hz,1H),6.99(t,J=7.4Hz,1H),6.94(d,J=8.3Hz,1H),3.76(s,3H),3.63(s,3H),2.51(s,3H),1.75(s,3H). 13 C NMR (150MHz, CDCl3) δ165.8,157.0,153.1,146.2,139.5,136.3,136.0,129.8,129. 8,129.1,128.6,126.4,125.4,124.1,122.1,120.7,110.8,55.9,51.2,27.3,25.4.

[0105] From compound No. 24, light yellow solid 24b and yellow solid 24c (24b: 266.7 mg, 77%, 24c: 60.2 mg, 17%, total yield 94%) were obtained. 1 H NMR (600MHz, CDCl3) δ7.70 (d, J = 8.0Hz, 2H), 7.42 (d, J = 7.9Hz, 2H), 7.28-7.22 (m, 6H), 2.11 (s, 3H), 1.45 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 168.1, 147.1, 143.7, 137.4, 129.3, 129.3, 129.2, 128.8, 128.44, 128.35, 126.21, 126.19, 126.17, 126.15, 21.4, 19.5. Compound 24c: 1 H NMR (600MHz, CDCl3) δ7.96(d,J=7.5Hz,1H),7.80(d,J=7.6Hz,1H),7.66(d,J=7.9Hz, 2H),7.40(d,J=7.9Hz,2H),7.36-7.30(m,2H),3.64(s,3H),2.52(s,3H),1.66(s,3H). 13 C NMR (150MHz, CDCl3) δ165.5,154.1,147.3,143.4,138.8,136.3,135.9,130.2,129.3,126.9,126.1,125.1,125.1,124.2,122.4,51.4,27.3,26.9.

[0106] Compound No. 25 can obtain a milky white solid 25b and a yellow solid 25c (25b: 233.7 mg, 74%, 25c: 84.0 mg, 25%, total yield 99%). 1 H NMR(600MHz, CDCl3)δ7.44-7.36(m,3H),7.29(dd,J=9.7,6.2Hz,2H),7.27-7.24(m,3H),7.19(dd,J=9.8,5.2Hz,3H), 2.64-2.59(m,2H),1.85-1.79(m,2H),1.70(dt,J=11.9,6.1Hz,2H),1.54(dd,J=11.5,6.0Hz,2H),1.41-1.37(m,2H). 13 C NMR (150 MHz, CDCl3) δ 168.6, 149.0, 141.9, 134.7, 133.7, 129.9, 129.2, 129.1, 129.0, 128.5, 128.4, 128.2, 127.9, 30.8, 29.0, 28.3, 28.0, 26.3. Compound 25c: 1H NMR(600MHz, CDCl3)δ7.92(d,J=7.6Hz,1H),7.85(d,J=7.8Hz,1H),7.37-7.25(m,8H),3.63(s,3H),3.0 9-3.04(m,2H),2.04-2.00(m,2H),1.89-1.83(m,2H),1.60(dd,J=11.5,5.8Hz,2H),1.45-1.39(m,3H). 13 C NMR (150MHz, CDCl3) δ165.9,164.1,148.9,139.5,139.25,136.0,134.7,129.7,12 8.8,127.9,127.3,126.7,125.6,123.9,122.1,51.3,35.4,34.6,28.9,28.5,25.9.

[0107] From compound No. 26, a milky white solid 26b and a yellow solid 26c (26b: 111.5 mg, 37%, 26c: 166.7 mg, 53%, total yield 91%) were obtained. Compound 26b: 1 H NMR (600MHz, CDCl3) δ7.67(s,1H),7.19(s,2H),3.92(s,6H),3.88(s,3H),2.06(s,3H),2.02(s,3H). 13 C NMR (150 MHz, CDCl3) δ 169.1, 153.5, 144.5, 139.2, 130.9, 128.2, 125.7, 123.1, 104.4, 61.1, 56.4, 19.1, 19.0. Compound 26c: 1 H NMR (600MHz, CDCl3) δ7.65(s,1H),7.54(s,1H),3.95(s,3H),3.89(s,3H),3.88(s,3H),3.80(s,3H),2.54(s,3H),2.36(s,3H). 13 C NMR (150MHz, CDCl3) δ165.6,153.3,152.2,149.2,141.1,137.5,137.2,135.5,128.0,120.5,102.1,61.4,61.0,56.3,51.5,26.2,26.0.

[0108] Example 2

[0109] In this example, the organic synthesis method in Example 1 was applied to the total synthesis of the active natural product anmindenol A. The natural product anmindenol A can effectively inhibit inducible nitric oxide synthase (iNOS) without showing any obvious cytotoxicity, so developing a simple and efficient synthesis method for it has high medicinal value.

[0110] Using this synthetic method as the key strategy, the total synthesis of anmindenol A can be achieved in three steps. The steps are simple and efficient. The following is the total synthesis route of anmindenol A:

[0111]

[0112] The specific synthesis steps of the present embodiment are as follows:

[0113] [Synthesis Step 1] The reagent 4-methyl-1-pentyn-3-ol (100 mg, 1.02 mmol) and methyl p-tolyldiazoacetate (compound 1, 775 mg, 4.07 mmol) were dissolved in 10 ml of DCE, irradiated with 470 nm blue light, reacted at room temperature, reacted for 12 hours, and monitored the reaction progress by TLC. After the reaction, the excess solvent was removed by vacuum concentration using a rotary evaporator, and the product was purified and separated on a chromatography column, with the developing solvent being PE:EA=10:1 to PE:EA=6:1, to obtain compound 27a as a yellow viscous liquid (257.4 mg, 81%).

[0114] [Synthesis step 2] Under inert gas protection, compound 27a (1.49 mmol, 388.5 mg) was dissolved in toluene (8 ml) in a 25 ml reaction tube, and then BF3·OEt2 (4.48 mmol, 0.55 ml) was slowly added dropwise at room temperature. The temperature was then raised to 120°C and the reaction was reacted for 1 h. The reaction progress was monitored by thin layer chromatography (TLC). After the reaction, 20 ml of saturated sodium bicarbonate aqueous solution was added to quench, and the mixture was extracted with EA three times (10 ml×3). The organic phase solvents were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure using a rotary evaporator to remove excess solvent. The product was purified and separated on a chromatography column with a developing solvent of PE:EA=80:1 to PE:EA=20:1 to obtain light yellow solid 27b and light yellow solid 27c (27b: 87.8 mg, 25.77%; 27c: 152.7 mg, 42.3%, total yield 68.07%).

[0115] [Synthesis Step 3] Under inert gas protection, compound 27c (0.25mmol, 60mg) was dissolved in DCM (5ml) in a 25ml reaction tube, and then DIBAL-H (1M, 0.62mmol, 0.62ml) was slowly added dropwise at -40°C. After the addition was completed, the reaction was stirred at this temperature for 4h, and the reaction progress was monitored by thin layer chromatography (TLC). After the reaction was completed, 15ml of saturated sodium bicarbonate aqueous solution was added to quench, and DCM was extracted 3 times (20ml×3), the organic phase solvent was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure with a rotary evaporator to remove excess solvent, and the product was purified and separated on a chromatographic column, and the developing solvent was PE:EA=6:1, and a white solid anmindenol A (26.3mg, yield 49%) was obtained. NMR characterization of natural product anmindenol A: 1 H NMR (600MHz, CDCl3) δ7.41(s,1H),7.21(d,J=7.6Hz,1H),7.06(d,J=7.7Hz,1H),6.70(s,1H),6.40(d ,J=9.9Hz,1H),4.76(s,2H),3.04(ddt,J=13.1,9.8,6.6Hz,1H),2.40(s,3H),1.16(d,J=6.7Hz,6H). 13 C NMR (150MHz, CDCl3) δ138.64,138.49,138.11,137.12,136.45,135.18,127.70,120.51,120.02,118.82,66.36,29.72,23.43,21.74,21.12.

[0116] Example 3

[0117] In this embodiment, the organic synthesis method in Example 1 is applied to the synthesis of the anti-inflammatory drug rofecoxib; rofecoxib is a non-steroidal anti-inflammatory drug, a selective inhibitor of cyclooxygenase-2, and is clinically used for osteoarthritis, acute pain and primary dysmenorrhea. Therefore, developing a novel, concise and efficient synthesis method for it has high medicinal value.

[0118] Using this synthetic method as the key strategy, the synthesis of rofecoxib can be achieved in three steps. The steps are simple and efficient. The following is the total synthetic route of rofecoxib:

[0119]

[0120] The specific synthesis steps of the present embodiment are as follows:

[0121] [Synthesis step 1] The known compound 2 (500 mg, 2.10 mmol) and methyl phenyldiazoacetate (compound 3, 1.11 g, 6.30 mmol) were dissolved in 25 ml of DCE, irradiated with 470 nm blue light, reacted at room temperature for 12 h, and the reaction progress was monitored by thin layer chromatography (TLC). After the reaction, the excess solvent was removed by vacuum concentration using a rotary evaporator, and the product was purified and separated on a chromatography column, with the developing solvent being PE:EA=6:1 to PE:EA=4:1, to obtain compound 28a as a yellow solid (811.6 mg, 82%);

[0122] [Synthesis Step 2] Under inert gas protection, in a 25 ml reaction tube, compound 28a (1.50 mmol, 579.7 mg) was dissolved in toluene (10 ml), and then BF3·OEt2 (4.50 mmol, 0.56 ml) was slowly added dropwise at -20°C, and then the reaction was continued at -20°C for 4 h, and the reaction progress was monitored by TLC. After the reaction was completed, 30 ml of saturated sodium bicarbonate aqueous solution was added to quench, and EA was extracted 3 times (30 ml×3), the organic phase solvent was combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure with a rotary evaporator to remove excess solvent, and the product was purified and separated on a chromatographic column, and the developing solvent was PE:EA=20:1 to PE:EA=10:1, and a light yellow solid 28b and a light yellow solid 28c (28b: 313.7 mg, 59%; 28c: 182.4 mg, 33%, total yield 92%) were obtained. Compound 28b: 1 H NMR (600MHz, DMSO-d6) δ7.30-7.21(m,7H),7.02(t,J=5.7Hz,2H),3.81-3.74(m,3H),2.00(d,J=22.2Hz,3H),1.44(d,J=17.4Hz,3H); 13 CNMR(150MHz,DMSO-d6)δ167.42,159.64,149.23,143.61,129.89,129.73,12 8.91,128.27,128.06,126.43,125.51,124.44,114.42,55.17,20.80,18.72.

[0123] Compound 28c: 1H NMR(600MHz,DMSO-d6)δ7.85-7.78(m,1H),7.78-7.71(m,1H),7.34-7.26(m,2H),7.19 -7.08(m,2H),7.00-6.92(m,2H),3.79(s,3H),3.56(s,3H),2.47(s,3H),1.67(s,3H). 13 C NMR(150MHz,DMSO-d6)δ165.06,158.60,154.95,147.51,138.41,135.36,135.25,130.0 4,129.78,128.98,126.35,125.62,124.13,121.15,113.52,55.05,51.11,26.87,26.07.

[0124] [Synthesis step three] Retro-aldol condensation reaction: In a 25 ml reaction tube, compound 28b (0.42 mmol, 150 mg) was dissolved in a mixed solution of DMF (N, N-dimethylformamide) (3 ml) and water (1 ml), p-toluenesulfonic acid (0.63 mmol, 108.5 mg) was added, and then the temperature was raised to 100 ° C for 12 h, during which the reaction progress was monitored by thin layer chromatography (TLC). After the reaction was completed, 15 ml of saturated sodium bicarbonate aqueous solution was added to quench, and EA was extracted 3 times (20 ml × 3), the organic phase solvent was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure with a rotary evaporator to remove excess solvent, and the product was purified and separated on a chromatographic column, and the developing solvent was PE: EA = 3: 1, and a light yellow solid rofecoxib (110.9 mg, yield 84%) was obtained. Rofecoxib structural characterization: 1 H NMR (600MHz, DMSO-d6) δ8.03-7.89(m,2H),7.66-7.56(m,2H),7.48-7.38(m,3H),7.40-7.27(m,2H),5.42(s,2H),3.25(s,3H). 13 C NMR (150MHz, DMSO-d6) δ172.62,156.07,141.99,135.72,129.80,129.13,128.99,128.81,128.69,127.45,126.90,70.86,43.16.

Claims

1. A method for preparing γ-vinylidene-butenoic acid lactones and / or benzofulvene compounds, characterized in that: The preparation of the γ-vinylidene-butenoic acid lactone and benzofulvene compounds is to place a cyclopropenyl alcohol derivative a with different substitutions in a reaction solvent, then add an acid for catalysis, and after the reaction, quench, extract, concentrate, and column chromatography, to obtain a γ-vinylidene-butenoic acid lactone compound b and a benzofulvene compound c respectively; The structural formulas of the cyclopropenyl alcohol derivatives with different substitutions are shown in the following table: The reaction solvent is one or more of toluene, benzene, xylene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, ethyl acetate and n-hexane; The acid is a protonic acid or a Lewis acid, including: CH3SO3H, p-TsOH, Cu(OTf)2, Yb(OTf)3, In(OTf)3, Hf(OTf)4, TiCl4, FeCl3, AlCl3, BF3·OEt2.

2. A method for preparing γ-vinylidene-butenoic acid lactones and / or benzofulvene compounds, characterized in that: The preparation route of the benzofulvene natural product anmindenol A is as follows: The specific preparation method includes: Step 1: Dissolve 4-methyl-1-pentyn-3-ol and methyl p-tolyldiazoacetate in DCE, react under blue light and room temperature, remove excess solvent after the reaction, and purify and separate to obtain compound 27a; Step 2: Under inert gas conditions, the compound is dissolved in toluene, BF3·OEt2 is added dropwise, and the mixture is reacted at a constant temperature; after the reaction, the mixture is quenched, extracted, dried, and filtered, and then the excess solvent is removed and purified to obtain compound 27b and compound 27c; Step 3: Compound 27c is prepared into a solution, DIBAL-H is added dropwise to the solution of compound 27c at -40°C and stirred, and after the reaction, the solution is quenched, extracted, dried and filtered, and then the excess solvent is removed and purified to finally obtain the Anmindenol A.

3. A method for preparing γ-vinylidene-butenoic acid lactones and / or benzofulvene compounds, characterized in that: The preparation route of γ-vinylidene-butenoic acid lactone compound rofecoxib is as follows: The specific preparation method includes: S1: irradiating a solution containing compound 2 and compound 3 under blue light, reacting at room temperature, removing excess solvent after the reaction, and purifying and separating to obtain compound 28a, wherein compound 28a is a yellow solid; The compound 2 is The compound 3 is S2: Compound 28a is made into a solution, and BF3·OEt2 is added dropwise to the solution of compound 28a at a constant temperature for reaction. After the reaction, the solution is quenched, extracted, dried and filtered, and then the excess solvent is removed and purified to obtain compound 28b and compound 28c; S3: Retro-aldol condensation reaction: Compound 28b is prepared into a solution of compound 28b, mixed with toluenesulfonic acid to obtain a reaction mixture, and the reaction mixture is allowed to react at a constant temperature. After the reaction, the mixture is quenched, extracted, dried and filtered, excess solvent is removed, and then purified and separated to finally obtain rofecoxib.

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